Antigen-provoked polarization of CD4+ T cells along the Th1 pathway is often associated with autoimmune and chronic inflammatory diseases, whereas extreme skewing of the response toward a Th2 phenotype has been linked to atopy and allergic diseases. Intense interest in the underlying molecular mechanisms that control polarization has revealed a contingent of regulatory transcription factors, which not only help to define these pathways but also suggest potential sites for interventional tactics. Moreover, the recent identification of transcription factors specifically associated with CD4(+)CD25+ regulatory T-cells provides new clues regarding manipulation of this population in pursuit of directed immune regulation. Continued unraveling of the pathways underlying the development of deleterious immune responses and their control will guide new avenues of investigation and intervention.